Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6
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Yu-Chun Hsiao1,*, Ming-Hsin Yeh2,*, Yun-Ju Chen3,4, Ju-Fang Liu5, Chih-Hsin Tang6,7,8, Wei-Chien Huang1,8,9,10
1The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan
2Department of Surgery, Chung-Shan Medical University Hospital, Taichung, Taiwan
3Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
4Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan
5Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
6Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
7Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
8Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
9Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan
10Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
*These authors have contributed equally to this work
Wei-Chien Huang, e-mail: firstname.lastname@example.org
Keywords: lapatinib, IL-6, migration, microRNA, Raf-1
Received: April 23, 2015 Accepted: October 02, 2015 Published: October 12, 2015
Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3′UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.
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